The Impact of reference pricing on prescribing patterns, costs, and health services utilization of proton pump inhibitors: A quasi-experimental study in British Columbia, Canada.

INTRODUCTION: The Reference Drug Program (RDP) was established to steer patients toward equally safe and cost-effective medication under British Columbia's public drug coverage. Each RDP class covers at least one reference drug, and non-reference drugs are reimbursed up to the cost of the reference drug. In 2016, the RDP updated to include proton pump inhibitors (PPIs). This study evaluated the impact on drug expenditures, prescription patterns, and health services utilization. METHODS: We identified a cohort of individuals covered by Fair Pharmacare who used PPIs, and a control group of H2 Blockers users. We used interrupted time series analysis on administrative data from June 2014 to December 2019 on the following outcomes: new users, day supply, expenditures, drug costs, reference drug use, and physician visits and costs. RESULTS: The RDP had little impact on overall PPI use patterns. We did not observe any changes in reference drug uptake, new users, physician visits, cost-savings, or significant changes to days supplied post-policy. Cost expenditure results were likely biased due to co-occurring changes to drug prices. CONCLUSION: Inclusion of PPIs to the RDP saw no cost-savings for the provincial drug program and had little impact on prescribing patterns. Overall, our findings are consistent with existing evidence that the RDP is safe for similar therapeutic alternatives, but the impact on PPI costs remains unclear.

Is schedule IV suvorexant an appropriate reference drug of abuse to use in preclinical abuse liability testing in the rat?

The abuse potential of novel CNS-active drug candidates with low specificity for known receptors involved in abuse might be complex to test preclinically relative to an appropriate reference drug of abuse. Suvorexant, a Schedule IV dual orexin receptor antagonist was investigated for its potential use as a reference drug in Drug Discrimination Learning (DDL) studies. Firstly, toxicokinetic properties of suvorexant were determined in male and female rats after single oral doses of 160 and 325 mg/kg in MC and PEG400. Thereafter the subjective effects of suvorexant at 325 mg/kg versus vehicle were evaluated in a DDL paradigm and plasma exposures were measured. Mean maximum plasma exposures in male rats after a single dose of 325 mg/kg suvorexant were 2.5- (MC) to 10.5-fold (PEG400) the human exposure at supratherapeutic doses of 40 mg q.d. (Cmax:1.1 µM), and 4.9- (MC) to 20.8-fold (PEG400) the approved maximum human efficacious dose (20 mg q.d.; 0.557 µM). Training male rats at 325 mg/kg in the DDL study however did not result in discriminative stimulus generalisation versus respective vehicles. Suvorexant, a Schedule IV dual orexin receptor antagonist failed to serve as a robust reference drug of abuse in the DDL paradigm in rats despite appropriate exposures.

Quality grade evaluation of Nvjin Pills based on traditional Chinese medicine reference drug and network pharmacology of target-focused compounds.

To improve the effectiveness of marketed drugs related to active ingredients, it is necessary to designate a more unified quality evaluation standard. Taking Nvjin Pills as an example, this study reported the development of a novel principle of analysis in traditional Chinese medicine. The core of the experiment is to prepare three batches of traditional Chinese medicine reference drugs by high-quality Chinese materia medica. The active ingredients identified in the herbal formula including glycyrrhizic acid, cinnamaldehyde, paeonol, baicalin, hesperidin, paeoniflorin, and ferulic acid were analyzed in traditional Chinese medicine reference drugs by the high-performance liquid chromatography method combined with wavelength switching. The simple prediction results of network pharmacological analysis verified the feasibility and reliability of the established quantitative analysis method for seven target-focused compounds in Nvjin Pills, which were recommended as candidate indicators for quality evaluation ultimately. Using the seven target-focused compounds as the scientific ruler, quality grade specifications of Nvjin Pills were proposed by comprehensive analysis. Accordingly, 16, 47, and 13 batches of samples were primarily graded as first grade, second grade, and unqualified grade, respectively. This study will provide a chemical basis for quality control of Nvjin Pills, which is necessary for the production process of pharmaceutical development.

Within-subject pharmacokinetic variability has a strong influence on individual exposure ratios in bioequivalence studies, hence on drug formulation interchangeability.

INTRODUCTION: Bioequivalence between a reference and a generic drug is based on the hypothesis that a ± 20% change in blood exposure (or ± 10% for drugs with narrow therapeutic index, NTI) following the generic/reference switch will not have any therapeutic consequences. However, the individual exposure ratio between generic and reference can be higher than 1.20 (or 1.10). This study aims to analyse the different parameters influencing the individual exposure ratio, hence the conditions for reference/generic interchangeability. METHODS: Bioequivalence studies with a double cross-over design for a virtual drug were simulated using 100 random sets of 12, 24, 48 or 100 pairs of areas under the curve (AUC), varying the generic/reference AUC geometric mean ratios between 0.80 and 1.25 and the within-subject exposure variance of the reference and the generic formulations. RESULTS: The proportion of subjects with an exposure generic/reference ratio outside the ± 10% or ± 20% acceptance intervals increases when (1) the reference within-subject variance increases; (2) the ratio of the generic within-subject variance on the reference within-subject variance increases; and (3) the generic/reference mean AUC ratio diverges from 1.0. When only considering replicated administrations of the reference, the individual exposure ratio increases with the within-subject variance, yielding values outside the usually accepted individual exposure ratio range of 0.5 to 2 for drugs with narrow therapeutic index as soon as the within-subject variance standard deviation is ≥ 0.25 (equivalent to within-patient CV% > 25%). CONCLUSIONS: Interchangeability between reference and generic formulations, especially for drugs with narrow therapeutic index can only be assumed if, the within-subject variance of generic is less or equal to the within-subject variance of reference or, if this is not the case, if the distribution of the generic/generic individual exposure ratios is included within the therapeutic margins of the reference drug.

[Use of biosimilars in the treatment of rheumatoid arthritis : An overview]. / Einsatz von Biosimilars in der Behandlung der rheumatoiden Arthritis : Ein Überblick.

Biologics have been an integral part of the treatment of rheumatoid arthritis for approximately 20 years. As patents for pharmaceuticals generally expire after 10 years, in recent years biosimilars have come onto the market. Many studies have shown that they are an equivalent alternative to the reference drug with comparable safety and efficacy. In some cases, they even showed lower rates of adverse drug reactions compared to the reference drugs. Furthermore, considerable costs can be saved by biosimilars, which amount to an annual three-digit million sum in Germany alone. Large regional differences in the prescription frequency of biosimilars in Germany can be identified, which are also reflected in the savings potential. A switch to a biosimilar is possible and desirable with the involvement of the patient. In this sense, the initial prescription of a biosimilar instead of the reference drug is also to be advocated.

Chemometric Analysis of HPLC Fingerprint of Triterpenoids in Different Ganoderma Preparations Based on Reference Drug / 中国药学杂志

OBJECTIVE: To establish a method combining triterpenoids fingerprint with chemometric analysis based on reference drug, and determine 89 batches of samples to evaluate the quality of Ganoderma preparations. METHODS: The samples were extracted by ultrasonic with methanol, chromatography was performed on Agilent TC C18(2) column (4.6 mm×250 mm, 5 μm) with gradient elution with acetonitrile and 0.02% phosphoric acid aqueous solution. The detection wavelength was set at 254 nm. Principal component analysis and HCA heatmap were used for data analysis. RESULTS: The chromatographic fingerprint has 56 characteristic peaks. By comparing the samples with the reference drug, it was found that Ganoderma preparations were produced using Ganoderma lucidum by almost all manufacturers. Principal component analysis, HCA heatmap analysis and similarity analysis divided the samples into three categories. The first type had characteristic peaks and peak areas which were consistent with the reference drug, and the quality was better. The second type had characteristic peaks which consistent with the reference drug, but the peak areas were smaller and the quality was medium. And the third type was different from the reference drug, which was the problem sample. The strong characteristic peaks for classification of different samples were peak 26, peak 31, peak 24, peak 32 and peak 18. CONCLUSION: The method is comprehensive, accurate and specific, and it can be used for comprehensive quality evaluation of triterpenoids in Ganoderma preparations.

[Determination and risk assessment of heavy metals and harmful elements residues in Niuhuang Qingwei Pills based on ICP-MS].

To achieve a comprehensive understanding of heavy metals and harmful elements residues in Niuhuang Qingwei Pills,49 samples from 18 manufactures were collected from 31 provinces in China.Risk assessment and control preparations were applied innovatively in evaluation of exogenous pollution in traditional Chinese Medicine.Determination methods for Pb,Cd,As,Hg and Cu were established by inductively coupled plasma mass spectrometry(ICP-MS).Based on the procedures including hazard identification,hazard characterization,exposure assessment and risk characterization,risk assessment was performed and residual limits for Pb,Cd,As,Hg and Cu in the drug were formulated.The results showed that the hazardous quotients(HQ) of the elements were decreased in the following order:Pb>As>Cu>Hg>Cd,and the total hazardous index(HI) of heavy metals and harmful elements in Niuhuang Qingwei Pills was above 1,implying health risk of the drug.Under the proposed limits,5 elements in the control preparation as well as Cd and Cu in the samples were within the limits range,but the excess rates of Pb,As and Hg in the samples were 12%,12% and 14%,respectively.For the first time,basic steps for risk assessment of Chinese patent medicine were established,which provided model and reference for risk assessment and limit formulation of other drugs.

Determination and risk assessment of heavy metals and harmful elements residues in Niuhuang Qingwei Pills based on ICP-MS / 中国中药杂志

To achieve a comprehensive understanding of heavy metals and harmful elements residues in Niuhuang Qingwei Pills,49 samples from 18 manufactures were collected from 31 provinces in China.Risk assessment and control preparations were applied innovatively in evaluation of exogenous pollution in traditional Chinese Medicine.Determination methods for Pb,Cd,As,Hg and Cu were established by inductively coupled plasma mass spectrometry(ICP-MS).Based on the procedures including hazard identification,hazard characterization,exposure assessment and risk characterization,risk assessment was performed and residual limits for Pb,Cd,As,Hg and Cu in the drug were formulated.The results showed that the hazardous quotients(HQ) of the elements were decreased in the following order:Pb>As>Cu>Hg>Cd,and the total hazardous index(HI) of heavy metals and harmful elements in Niuhuang Qingwei Pills was above 1,implying health risk of the drug.Under the proposed limits,5 elements in the control preparation as well as Cd and Cu in the samples were within the limits range,but the excess rates of Pb,As and Hg in the samples were 12%,12% and 14%,respectively.For the first time,basic steps for risk assessment of Chinese patent medicine were established,which provided model and reference for risk assessment and limit formulation of other drugs.

Fingerprint Study and Primary Quality Evaluation of Niuhuang Qingwei Pills Based on UPLC and Reference Drug / 中国药学杂志

OBJECTIVE： To apply reference drug in the fingerprint study of Niuhuang qingwei pills, and perform primary evaluation of the quality grade of the samples. METHODS： Ultra performance liquid chromatography (UPLC) separation was performed on an AQUITY UPLC BEH C18 column with gradient elution using acetonitrile (containing 0.5% formic acid)-0.5% formic acid at a flow rate of 0.2 mL•min-1. The injection volume was 2 μL and the column temperature was maintained at 40 ℃. The detection wavelength was set at 254 nm. By comparing with reference substances and the reference herbal materials, characteristic peaks and their ascriptions were investigated. Using Niuhuang qingwei pills reference drug as the accompanying physical control, the similarities of the fingerprints of 49 batches of samples from 18 manufacturers were calculated, and the quality grades were evaluated. RESULTS： The similarities of all samples fell within the range of 0.76-0.98. The similarities of 49 samples were above 0.75 and met the second-grade limit. The similarity of 24 samples were above 0.90 and met the first-grade limit. CONCLUSION： The method is simple, accurate and rapid. It can be used for the quality control and grade evaluation of Niuhuang qingwei pills, which provides reference for the quality grade research of Chinese patent medicines.

[In vitro equivalence evaluation of betahistine generic medicinal products as a tool potentially determining the efficacy of pharmacotherapy]. / Otsenka ékvivalentnosti in vitro vosproizvedennykh preparatov betagistina kak instrumenta, potentsial'no opredeliaiushchego éffektivnost' farmakoterapii.

AIM: To compare release parameters of various betahistine drugs in vitro using a comparative dissolution kinetics test. MATERIAL AND METHODS: Objects of research are solid dosage forms (tablets) containing betahistine in a dose of 24 mg permitted for medical use in the Russian Federation. A method of comparative dissolution kinetics test was carried out as follows. The study was performed on a paddle stirrer at a speed of 50 rpm in three different pH dissolution media (pH 1.2, 4.5, 6.8), simulating the main sections of the digestive tract in which the active ingredient was decomposed, released and absorbed. This was performed in a quality controlled environment using a citrate buffer solution with pH 6.8. The time points for sampling the medium were 10 min, 15 min, 20 min and 30 min. RESULTS: The results of betahistine release were significant (RSD<10%) for all time points, except the first time point (RSD<20%). Regardless of pH, there was a complete release (≥85% over 15 minutes, <10%) of betahistine from betaserc, 24 mg, tablets (manufactured by Mylan Laboratories SAS). The dissolution profiles of betahistine in other investigational drugs did not show complete drug release (parameter <85% in 15 minutes, <10%) in different pH media. Therefore, dissolution profiles of the studied drugs were not comparable to the reference profile. CONCLUSION: Starting from 10 minutes, the reference drug of betahistine (betaserc, 24 mg) has a consistently higher release at different pH levels (representing the various stages of gastric digestion), vs. other studied generic analogues showing significantly lower levels of betahistine release. None of the studied drugs were found to be equivalent in vitro.

Consistency evaluation of domestic generic rifampicin capsules and reference drug in vitro / 中国药科大学学报

@#This study was to evaluate quality consistency of domestic generic and reference preparations. Content and related substances of domestic generic preparations and reference preparation were inspected according to Chinese Pharmacopeia 2015. Then the basic solution for determining dissolution curve was established through preliminary experiment and validation for determination. The dissolution curves of domestic rifampicin capsules and reference preparation were compared in four dissolution mediums: HCl(pH 1. 2), PBS(pH 4. 0), PBS(pH 6. 8)and pure water, respectively. Results showed that the content and related substances of domestic generic and reference preparations complied with the quality standard, but impurity profile displayed that impurities in domestic generic preparations were less than those in the reference preparation, with the content of rifampin quinine being especially less. Furthermore, dissolution of domestic generic and reference preparations were compared, and their dissolution curves were not similar. It is suggested that consistency between domestic rifampicin capsules and reference preparation should be evaluated by bioequivalence test.

[Guideline principle and technical requirement for preparing traditional Chinese medicine reference drug].

Traditional Chinese medicine (TCM) reference drug is a new form of TCM standard reference substance. The purpose of this guideline is to guide the establishment of the reference drug and standardize its investigation and application in national drug standards. Definition of TCM reference drug was specified and relating guideline and technical requirement were introduced in this paper. Its application in quality control of TCM was analyzed and the developing train was proposed. There is a wide prospect for the application of reference drug in quality control of TCM. Thus it has practical significance to explore and conduct the quality evaluation system by using TCM reference drug as the reference substance.

Guideline principle and technical requirement for preparing traditional Chinese medicine reference drug / 中国中药杂志

Traditional Chinese medicine (TCM) reference drug is a new form of TCM standard reference substance. The purpose of this guideline is to guide the establishment of the reference drug and standardize its investigation and application in national drug standards. Definition of TCM reference drug was specified and relating guideline and technical requirement were introduced in this paper. Its application in quality control of TCM was analyzed and the developing train was proposed. There is a wide prospect for the application of reference drug in quality control of TCM. Thus it has practical significance to explore and conduct the quality evaluation system by using TCM reference drug as the reference substance.

Is a Biologic Produced 15 Years Ago a Biosimilar of Itself Today?

Much of the testing required for the regulatory approval of a biosimilar is focused on proving that the new drug is sufficiently similar to the reference biologic in structure, pharmacokinetics or pharmacodynamics, clinical efficacy, and safety. However, the reference drug may itself have gone through some changes in the years since its approval, including those caused by alterations in the manufacturing process. Do these changes increase the risk that the reference drug may cause unexpected outcomes? It is up to the US Food and Drug Administration to decide whether the changes merit the need for additional studies to confirm that the drug meets the structural or clinical outcomes standard for the reference agent. Although it is extremely rare, a change in the production of one biologic drug (ie, epoetin alfa) did result in unanticipated serious immunologic side effects.

Demonstrating Value for Biosimilars: A Conceptual Framework.

BACKGROUND: The value proposition for biosimilars can be characterized as a concept that moves beyond the argument of cost reduction relative to the innovator biologic drug and into a framework that incorporates the diverse needs of key healthcare stakeholders during the transition from clinical development to commercialization in the marketplace. OBJECTIVES: To identify factors that facilitate and inhibit the development, commercialization, and adoption of biosimilars, and to recommend modifications in program design that are likely to support the demonstration of the value of biosimilars for payers, providers, and patients. METHODS: The primary data sources for this article include surveys conducted by Boston Healthcare Associates with payers and clinicians in the United States and the European Union 5 markets and blinded international protocol feasibility assessments completed by Worldwide Clinical Trials. Survey methodology used either convenience or purposeful sampling as appropriate, with participants extracted from diverse audiences, representative of those who generate or evaluate clinical data shaping the economic exchange and preferential status influencing physician adoption and patient access to biosimilars. Patient characteristics and psychosocial issues influencing patients' perception of small-molecule generics were extracted from the available literature to inform exploratory hypotheses, given the relative absence of such information for biosimilars. DISCUSSION: This article reviews the current evidence and summarizes results of surveys conducted with payers, providers, and drug investigation sites in the United States. Based on a review of published literature, as well as these survey results, conflicting and convergent demands exist for gathering data related to biosimilars. The motivations and data needs for these new agents are diverse, requiring adjudication of regulatory, economic, and clinical incentives beginning at program inception and extending through commercialization of the final biosimilar agent. CONCLUSIONS: The development and commercialization of biosimilars represent an international activity that can encounter unanticipated challenges, as well as opportunities to achieve clinical and commercial success. Evolving regulatory guidance mapped in relation to payer, physician, and patient sentiments may inform the biosimilar development program designs, implementation, and positioning of the new drug.